The longterm goal of this project is the identification and characterization of endophenotypes which interact with genes and with early environmental effects to produce the clinical syndrome of IC/PBS in the adult patient. Dissecting the complex symptom-based syndrome of IC/PBS into neurobiological endophenotypes, which are shaped by gene-early environment interactions, will enhance our understanding of its pathophysiology, of its relationship with other functional pain syndromes and affective disorders, and is required for the development of effective treatment approaches. Using psychophysical assessment techniques to characterize pain sensitivity, neurophysiological tests to asess emotional arousal, and functional brain imaging techniques to identify underlying brain circuits, this project aims to pursue this longterm goal in 3 specific aims in 150 IC/PBS patients (and 150 controls) and in a rodent stress model: A. Characterize brain circuits involved in pelvic pain processing and endogenous pain inhibition in IC/PBS. B. Characterize brain mechanisms involved in emotional arousal and central pain facilitation in IC/PBS. C. Characterize brain circuits in a rodent model of prenatal and adult stress. Neurobiological endophenotypes identified in each aim will be correlated with gene polymorphisms of signaling systems involved in pain processing and modulation, and in emotional and cognitive function, and early adverse life events. In Aim A, we will first characterize somatic pain sensitivity in IC/PBS using different types of pain stimuli. Using these pain stimuli, we will then identify alterations in brain circuits involved in the processing and endogenous inhibition of pain. In Aim B, we will characterize the role of affective modulation of the aoustic startle reflex, of a nociceptive spinal reflex (RIM) response, and of emotional arousal circuits in producing pain inhibition and facilitation. In Aim C, we will characterize the effect of prenatal stress, and of adult chronic stress on brain responses to bladder distension in the freely moving rat. This project is highly responsive to the RFA request to study small cohorts of patients to establish robust pheontypes, and to characterize the role of biologic, psychosocial and genetic vulneraility factors in IC/PBS. It interacts closely and in a synergistic fashion with Project 1 (which addresses the same question with a targeted epidemiological study) and with Project 3, which addresses spinal and peripheral (bladder) changes associated with the endophenotypes.